Spleen-targeted neoantigen DNA vaccine for personalized immunotherapy of hepatocellular carcinoma.

Neoantigens are emerging as attractive targets to develop personalized cancer vaccines, but their immunization efficacy is severely hampered by their restricted accessibility to lymphoid tissues where immune responses are initiated. Leveraging the capability of red blood cells (RBCs) to capture and present pathogens in peripheral blood to the antigen-presenting cells (APCs) in spleen, we developed a RBC-driven spleen targeting strategy to deliver DNA vaccine encoding hepatocellular carcinoma (HCC) neoantigen. The DNA vaccine-encapsulating polymeric nanoparticles that were intentionally hitchhiked on the preisolated RBCs could preferentially accumulate in the spleen to promote the neoantigen expression by APCs, resulting in the burst of neoantigen-specific T-cell immunity to prevent tumorigenesis in a personalized manner, and slow down tumor growth in the established aggressively growing HCC. Remarkably, when combined with anti-PD-1, the vaccine achieved complete tumor regression and generated a robust systemic immune response with long-term tumor-specific immunological memory, which thoroughly prevented tumor recurrence and spontaneous lung metastasis. This study offers a prospective strategy to develop personalized neoantigen vaccines for augmenting cancer immunotherapy efficiency in immune "cold" HCC.

Nickel-Catalyzed Selective C-H Cyanation via Aromatic Thianthrenium Salts.

Here, we report the first case of nickel-catalyzed C-H cyanation via arylthianthrenium salts. The reaction features the use of air-stable and inexpensive NiCl2·6H2O as a catalyst for the highly selective construction of cyanation products by aromatic pre-thianthrenation. The mechanism study shows that the formation of aryl radicals is involved. Also, this protocol can be applied to the late-stage functionalization of bioactive molecules and is readily scalable, further showcasing the synthetic utility.

Genetically engineered nanovesicles mobilize synergistic antitumor immunity by ADAR1 silence and PDL1 blockade.

Growing evidence has proved that RNA editing enzyme ADAR1, responsible for detecting endogenous RNA species, was significantly associated with poor response or resistance to immune checkpoint blockade (ICB) therapy. Here, a genetically engineered nanovesicle (siAdar1-LNP@mPD1) was developed as an RNA interference nano-tool to overcome tumor resistance to ICB therapies. Small interfering RNA against ADAR1 (siAdar1) was packaged into a lipid nanoparticle (LNP), which was further coated with plasma membrane extracted from the genetically engineered cells overexpressing PD1. siAdar1-LNP@mPD1 could block the PD1/PDL1 immune inhibitory axis by presenting the PD1 protein on the coating membranes. Furthermore, siAdar1 could be effectively delivered into cancer cells by the designed nanovesicle to silence ADAR1 expression, resulting in an increased type I/II interferon (IFN-ß/γ) production and making the cancer cells more sensitive to secreted effector cytokines such as IFN-γ with significant cell growth arrest. These integrated functions confer siAdar1-LNP@mPD1 with robust and comprehensive antitumor immunity, as evidenced by significant tumor growth regression, abscopal tumor prevention, and effective suppression of lung metastasis, through a global remodeling of the tumor immune microenvironment. Overall, we provided a promising translatable strategy to simultaneously silence ADAR1 and block PDL1 immune checkpoint to boost robust antitumor immunity.

Magnetically responsive nanoplatform targeting circRNA circ_0058051 inhibits hepatocellular carcinoma progression.

Circular RNAs (circRNAs) are a class of highly stable and closed-loop noncoding RNA that are involved in the occurrence and development of hepatocellular carcinoma (HCC). However, little is known about the therapeutic role of circRNAs in HCC. We found that high circ_0058051 expression was negatively correlated with the prognosis of HCC patients. Circ_0058051 knockdown attenuated the proliferation and colony formation, meanwhile inhibited migration of HCC cells. Circ_0058051 may be used as a target for HCC gene therapy. We synthesized a novel small interfering RNA (siRNA) delivery system, PEG-PCL-PEI-C14-SPIONs (PPPCSs), based on superparamagnetic iron oxide nanoparticles (SPIONs). PPPCSs protected the siRNA of circ_0058051 from degradation in serum and effectively delivered siRNA into SMMC-7721 cells. Meanwhile, intravenous injection of the PPPCSs/siRNA complex could inhibit tumor growth in the subcutaneous tumor model. In addition, the nanocomposite is not toxic to the organs of nude mice. The above results show that PPPCSs/si-circ_0058051 complex may provide a novel and promising method of HCC treatment.

Construction of Unsaturated Collagen Microsphere System Based on Hydrogen/Coordination Bond and Application.

In this paper, unsaturated collagen microspheres (CMA-Cr/ST) were constructed from vinyl collagen (CMA, which is from leather solid waste) and chromium/synthetic tannins (Cr/ST) through hydrogen and coordination bonds and grafted on polyamide nonwoven fiber by thiol-ene click chemistry to improve the moisture absorption and permeability of nonwoven. The results showed that when the quality ratio of CMA to Cr/ST was 1:1, the magnetic stirring time was 20 min with 250 rpm at room temperature, the surface and particle size distribution of the obtained microspheres were smooth and relatively uniform, and the average particle size was 2-3 µm. When the concentrations of the microspheres and the initiators were 6 and 0.006 wt %, the irradiation time was 4 h and the grafting rate of CMA-Cr/ST on the surface of polyamide fibers would reach 31.3%. The moisture absorption and permeability of the obtained microsphere-modified polyamide nonwoven fiber (CMA-Cr/ST-S-PA) were increased. It was found that the collagen microspheres were firmly modified on the polyamide fibers by moisture and heat resistance, wash resistance, and solvent resistance studies.

Nanoplatform Self-Assembly from Small Molecules of Porphyrin Derivatives for NIR-II Fluorescence Imaging Guided Photothermal-Immunotherapy.

Combinatorial photothermal and immunotherapy have demonstrated great potential to remove primary tumors, suppress metastases, and prevent tumor recurrence. However, this strategy still confronts patients with many limitations, such as complex components, sophisticated construction, and inadequate therapeutic efficacy. In this work, small molecules of porphyrin derivatives (PPor) which can self-assemble into monodispersed nanoparticles without supplement of any other ingredients or surfactants are developed. The formed PPor nanoparticles (PPor NPs) exhibit highly photothermal conversion efficiency of 70% and NIR-II luminous abilities originate from the strong intramolecular charge transfer (ICT) effect of D-A structure under 808 nm laser irradiation, thus achieving NIR-II fluorescence imaging guided photothermal therapy (PTT) against primary tumors with a high cure rate. More importantly, tumor-associated antigens (TAAs), together with damage-associated molecular patterns (DAMPs) released from PTT-treated cancer cells, are proved to elicit immune responses to some degree. After combination with programmed cell death-1 (PD-1) antibodies, a robust systematic antitumor immunity is generated to restrain both primary and abscopal tumors growth, prolong survival, and prevent pulmonary metastasis on an aggressive 4T1 murine breast tumor model. Thus, this study provides a promising therapeutic paradigm with porphyrin derivatives nano-assembly as phototheranostic agents for the treatment of aggressive tumors with high efficiency.

Self-assembled porphyrin polymer nanoparticles with NIR-II emission and highly efficient photothermal performance in cancer therapy.

The development of new organic nanoagents with extremely high photothermal conversion efficiency and good biocompatibility has gained considerable attention in the area of photothermal cancer therapy. In this work, we designed and synthesized a new porphyrin polymer (P-PPor) with donor-acceptor (D-A) structure. P-PPor displayed intense absorbance in the near-infrared (NIR) region with the maximum peak around at 850 â€‹nm. Under excitation of 808 â€‹nm, P-PPor demonstrated the significant fluorescence in the NIR-II region (λ max â€‹= â€‹1015 â€‹nm), with the fluorescence quantum yield of 2.19%. Due to the presence of hydrophilic PEG chains and hydrophobic alkyl chains in the conjugated skeleton, the amphiphilic P-PPor could self-assemble into the nanoparticles (P-PPor NPs) with good dispersibility in water and enhanced absorption in the NIR region. Moreover, P-PPor NPs exhibited quenched fluorescence because of the aggregation-caused quenching (ACQ) effect, resulting in the distinct photothermal effect. The photothermal conversion efficiency (PCE) of P-PPor NPs was measured as 66% under 808 â€‹nm laser irradiation, higher than most of PTT agents. The remarkable photothermal effect of P-PPor NPs was further demonstrated in vitro and in vivo using 4T1 tumor mode. Meanwhile, the NIR-II fluorescence imaging in vivo indicated the high distribution of P-PPor NPs in tumor site. These results suggested that P-PPor NPs could effectively damage the cancer cells in mice under 808 â€‹nm laser irradiation, and did not cause any obvious side effects after phototherapy. Thus, P-PPor NPs could be used as a potential agent in photothermal cancer therapy with high effectiveness and safety.

Construction of a Novel Substrate of Unfigured Islands-in-Sea Microfiber Synthetic Leather Based on Waste Collagen.

This study is to introduce waste collagen into an unfigured islands-in-sea microfiber nonwoven material, replacing the polyurethane impregnation section of the traditional manufacturing process with the collagen impregnation process. The modified collagen was first impregnated in polyamide/low-density polyethylene (PA/LDPE) fiber nonwoven to form a film. Then the low-density polyethylene component was extracted and dissolved in toluene, resulting in a collagen-based microfiber nonwoven substrate. Waste collagen was first modified to introduce C=C into the molecular chain to obtain vinyl collagen (CMA), and then the following film formation conditions for CMA were studied: 73% degree of substitution (DS), 3 h cross-linking time, and 0.005-0.01 wt % initiator concentration. Then, the preparation of CMA-PA/LDPE and toluene extraction processes were investigated. The optimum toluene extraction conditions were obtained as an extraction temperature of 85 °C and an extraction time of 110 min. The properties of the nonwoven materials were compared before (CMA-PA/LDPE) and after (PA-CMA) extraction. It was found that the homogeneity, tensile strength, and static moisture permeability of the PA-CMA materials prepared by CMA with 50 and 73% DS were all superior to those of PA/LDPE. In particular, the static moisture permeability of PA-CMA (691.6 mg/10 cm2·24 h) increased by 36.2% compared to the microfiber synthetic leather substrate currently in the market. Using scanning electron microscopy (SEM), the continuity of a film of PA-CMA with 73% DS was observed to be better and the fibers were differentiated and relatively tighter fiber-to-fiber gap. The studied novel green process can eliminate the large amount of dimethylformamide (DMF) pollution caused by the current solvent-based polyurethane impregnation process.

Synthesis of chitosan-based flame retardant and its fire resistance in epoxy resin.

A novel flame retardant CCD was synthesized by the condensation between cinnamalde and chitosan, followed by the addition reaction with 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide(DOPO), and CCD was named from the initials of the three raw materials. The intermediate product CC and the target product CCD was then characterized by infrared spectrometry and elemental analysis. The flame retardancy of EP thermosets modified by CCD was dramatically improved. Epoxy resin (EP) with 10wt% CCD passed vertical burning (UL-94) V-0 rating and possessed limited oxygen index (LOI) value of 31.6 %. Cone calorimeter test exhibited the introduction of 3.5g CCD into 35g EP decreased the total heat release by 38.8 % and decreased the total smoke product by 72.0 %. XPS, FTIR, SEM and Raman tests were proceeded to determine the char residue for EP/10 % CCD thermoset, and the results showed that char residue for EP/10 % CCD thermoset possessed dense and compact structure which played a positive effect in blocking the exchange of heat and gas.